On February 21, 1994, the Food and Drug Administration (FDA)
was notified of 14 possible cases from three different countries of
acute hepatitis C among persons who had received Gammagard
{Registered} *,
an intravenous immunoglobulin (IGIV) product manufactured by Baxter
Healthcare Corporation (Glendale, California). The company removed
Gammagard {Registered} from the worldwide market on February 23,
1994.
The American Red Cross removed Polygam {Registered} (IGIV
manufactured
by Baxter Healthcare from American Red Cross plasma) from the
market on
the same date. This report presents preliminary findings of an
evaluation of transmission of hepatitis C virus (HCV) infection
from
these products and guidelines for monitoring patients who may have
received them. **

As of July 19, 1994, CDC had received 112 reports from 24
states and Puerto Rico of possible cases of acute HCV infection in
recipients of IGIV; 111 were in persons who received
Gammagard {Registered}, and one was in a person who received
Polygam {Registered}. Medical and epidemiologic information and
serum samples for HCV serologic testing are being collected from
each person. The dates of onset (defined by occurrence of symptoms
or first abnormal alanine aminotransferase {ALT} value) for
suspected cases were from October 1993 through June 1994
(Figure_1.
Of 74 reported persons with possible HCV infection for whom
risk factor data (e.g., blood transfusion or injecting-drug use)
were available, 68 (92%) had receipt of IGIV as the only risk
factor for infection.

The median age of persons with reported cases was 37 years
(range: 2-84 years); 52% were female, and 63% received IGIV for
treatment of a primary immunodeficiency disorder (e.g.,
hypogammaglobulinemia). Of 62 persons tested at CDC for serologic
markers of viral hepatitis, 42 (68%) were positive for antibody to
HCV (anti-HCV), and none were positive for serologic markers of
acute hepatitis A or hepatitis B virus infection. Anti-HCV was
detected in 20 (53%) of 38 patients with a diagnosis of primary
immunodeficiency and in 21 (95%) of 22 patients with other
diagnoses. In blinded testing of serum specimens from 36 persons
with suspected cases, none were positive for antibody to human
immunodeficiency virus (HIV)-1 or HIV-2.

To assess the risk for HCV infection among persons who
received IGIV and to identify risk factors for infection, a cohort
study among persons exposed to different IGIV products at one
hospital and a case-control study of persons from throughout the
United States have been initiated. Lot-specific denominator data
needed to complete these analyses are not yet available from the
manufacturer. Preliminary analysis of the cohort study found 16
(7%) cases of HCV infection among 245 recipients of
Gammagard {Registered} (three persons with HCV infection had also
received other IGIV products within 6 months of onset). However, no
cases of HCV infection were found among 55 recipients who had
received only other IGIV products (p less than 0.05, two-tailed
Fisher exact test). Additional laboratory testing for HCV will be
performed on serum samples from infected persons and on samples of
implicated and nonimplicated lots of IGIV. Other cohort studies
will examine any association between HCV infection and receipt of
other IGIV products or intramuscular immune globulin (IGIM). In one
of these studies involving persons who received IGIM in 1993, no
anti-HCV seroconversions were found among 513 persons tested at
least 6 months after IGIM administration (95% confidence
interval=0-0.7%).

Editorial Note

Editorial Note: The temporal association of acute hepatitis C with
Gammagard {Registered} administration and the absence of other risk
factors among these patients indicate that HCV was most likely
transmitted by administration of Gammagard {Registered}. The report
of one possible case in a person who received only Polygam
{Registered} and had no other risk factors suggests that Polygam
{Registered} also may be associated with transmission of HCV.
Preliminary analysis of data from epidemiologic studies suggests
that HCV transmission is not related to the administration of
other IGIV products or IGIM, and there is no need for change in
the use of these products.

Since the 1940s, immune globulin products licensed in the
United States have been safely administered; these products
previously have not been known to be associated with the
transmission of bloodborne agents, including HIV. Cases of non-A,
non-B hepatitis (of which HCV is the primary etiologic agent) have
been previously associated with an unlicensed IGIV product used in
a clinical trial in the United States and with IGIV products
manufactured and distributed abroad; however, reasons for these
episodes of transmission (2) and the episodes described in this
report have not been determined. Since mid-May 1994, the approved
manufacturing process for both Gammagard {Registered} and
Polygam {Registered} includes a solvent-detergent treatment
designed
to inactivate contaminating viruses. Products manufactured with
this treatment should not pose a risk for HCV transmission to
recipients.

Chronic hepatitis develops in more than 60% of persons
infected with HCV (3). All patients who received Gammagard
{Registered} or Polygam {Registered} since April 1, 1993 (6 months
before the first reported case), should be screened for evidence
of HCV infection and the results interpreted according to the
algorithm established by the Public Health Service (PHS)
(Table_1).
Initial screening of these patients should include a test for
ALT activity and an FDA-licensed enzyme immunoassay (EIA) for
anti-HCV. All specimens repeatedly (two or more times) reactive for
anti-HCV should be tested using an FDA-licensed supplemental
anti-HCV assay to reduce the likelihood of false-positive EIA
results.

Because some patients will have a prolonged interval between
exposure and seroconversion to anti-HCV, patients who are anti-HCV-
negative but have abnormal ALT levels should be retested for
anti-HCV 3-6 months later. In most patients with normal immune
status, seroconversion occurs within 6 months after infection
(3,4). However, approximately 10% of HCV-infected patients with
normal immune status will be persistently negative for anti-HCV,
even after prolonged follow-up (3). Persons with immunodeficiency
disorders may be less likely to seroconvert or may have longer
intervals between infection and seroconversion than persons with
normal immune function.

For anti-HCV-negative persons with elevated ALT levels, the
diagnosis of hepatitis C is possible with the use of polymerase
chain reaction (PCR) for the detection of HCV RNA. However, PCR
assays, which are difficult and expensive to perform, should be
done only by experienced laboratories using specimens that have
been properly collected, stored, and handled. These assays are not
licensed by FDA.

Patients aged greater than or equal to 18 years with chronic
hepatitis C (abnormal ALT levels for more than 6 months) should be
evaluated for possible therapy with alpha interferon by a physician
experienced in its use (5). Patients should be informed that the
proportion of adults with chronic hepatitis C who sustain a
long-term response to alpha interferon is low (approximately 20%).
Although FDA has not licensed alpha interferon for patients aged
less than 18 years, they can be considered for therapy if entered
into an approved study protocol.

All patients with hepatitis C should be considered potentially
infectious. However, because of limited data on the risk of
household, sexual, and perinatal transmission and because testing
cannot determine infectivity, PHS does not recommend substantial
changes in behavior based on knowledge of infection status (1). PHS
recommends that household articles such as toothbrushes and razors
that could become contaminated with blood should not be shared, and
cuts or skin lesions should be covered to prevent the spread of
infectious secretions or blood (1). HCV transmission by sexual
contact appears to occur, but this route of transmission is much
less efficient than that for other bloodborne sexually transmitted
diseases (3). Although anti-HCV-positive persons should be informed
of the potential for sexual transmission, there are insufficient
data to recommend changes in current sex practices for persons with
one steady sex partner. To prevent many sexually transmitted
diseases, including hepatitis and HIV infection, persons with
multiple partners should follow safer sexual practices, including
reducing the number of sex partners and using barriers (e.g., latex
condoms) to prevent contact with body fluids. No evidence supports
advising against pregnancy based on anti-HCV status or using any
special treatments or precautions for pregnant women or their
offspring.

* Use of trade names and commercial sources is for identification only and does not imply endorsement by the Public Health Service or
the U.S. Department of Health and Human Services.

** Copies of this report and the Public Health Service
recommendations for medical evaluation and counseling of patients
with hepatitis C (1) are available from CDC's Hepatitis Branch,
Division of Viral and Rickettsial Diseases, National Center for
Infectious Diseases, Mailstop G-37, 1600 Clifton Road, NE, Atlanta,
GA 30333; or from CDC's Voice Information System, telephone (404)
332-2553.

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